2017 Grants - Van Skike

Candice Van Skike, Ph.D.
University of Texas Health Science Center at San Antonio
San Antonio, Texas

2017 Alzheimer’s Association Research Fellowship (AARF)

Does abnormal tau protein disrupt the function of blood vessels in the brain in Alzheimer’s disease?

Background
Alzheimer’s disease is characterized by the build-up of abnormal tau protein (“tangles”) and beta-amyloid (“plaques”) in the brain. Increasing evidence suggests that damage to the brain’s smallest blood vessels (microvasculature) may increase the risk of developing Alzheimer’s and related dementias. Scientists have shown that beta-amyloid can damage brain blood vessels, but very little is known about the effects of abnormal tau on microvascular function.

Research Plan
Candice Van Skike, Ph.D., and colleagues have planned a series of experiments to examine the effects of abnormal tau protein on brain vascular health. In previous studies, Dr. Van Skike found that small clumps of abnormal tau called oligomers are particularly toxic to endothelial cells – the cells that line blood vessels. For their current studies, the researchers will administer tau oligomers to endothelial cells collected from the microvessels of human brain tissue. They hypothesize that tau oligomers disrupt endothelial cell function by triggering abnormally high activity of a molecule called mammalian target of rapamycin (mTOR). They will determine if inhibiting mTOR activity using the drug rapamycin can prevent or reduce the negative effects of tau oligomers on endothelial cells. They will also study the health of blood vessels in the brains of mice that are genetically engineered to accumulate abnormal tau protein in the brain as they age. They will see if treating the mice with an antibody that clears tau oligomers from the brain can improve blood vessel function and preserve normal blood flow in the brain.

Impact
The results of these studies could address gaps in our understanding of how abnormal tau may disrupt brain blood vessel function in the early stages of Alzheimer’s to cause cognitive decline. This work could also identify new drug candidates that could help prevent or reverse tau-induced brain changes and potentially slow or halt the progression of Alzheimer’s disease.